Journal
CELL
Volume 155, Issue 6, Pages 1258-1269Publisher
CELL PRESS
DOI: 10.1016/j.cell.2013.11.008
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Funding
- European Commission
- NIH [U54 GM094618, F32 DK088392, 1DP2OD004744-01, P30CA014195]
- CIRM [RN1-00577-1]
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Molecular determinants regulating the activation of class B G-protein-coupled receptors (GPCRs) by native peptide agonists are largely unknown. We have investigated here the interaction between the corticotropin releasing factor receptor type 1 (CRF1R) and its native 40-mer peptide ligand Urocortin-I directly in mammalian cells. By incorporating unnatural amino acid photochemical and new click-chemical probes into the intact receptor expressed in the native membrane of live cells, 44 intermolecular spatial constraints have been derived for the ligand-receptor interaction. The data were analyzed in the context of the recently resolved crystal structure of CRF1R transmembrane domain and existing extracellular domain structures, yielding a complete conformational model for the peptide-receptor complex. Structural features of the receptor-ligand complex yield molecular insights on the mechanism of receptor activation and the basis for discrimination between agonist and antagonist function.
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